This application is in response to RFA MH-03-008 to form a National Cooperative Drug Discovery] Group for the Treatment of Mood Disorders or Nicotine Addiction (NCDDG-MD/NA) to work on] innovative drug discovery for these two disorders, and the development and validation of a putative new animal model of antidepressant activity. This project will involve an academic partner, The Scripps] Research Institute, La Jolla, California, and an industrial partner, Novartis Pharma AG, Basel, Switzerland. The pharmacological approach proposed is the development of gamma-aminobutyric acid B (GABAB) receptor positive modulators as antidepressants and/or aids to smoking cessation. Specific Aim 1 will involve the synthesis and refinement of GABAB receptor positive modulators with good selectivity for the GABAB receptor. Specific Aim 2 will involve experiments characterizing these GABAB positive modulators biochemically in human, rat and mouse GABAB receptor assays. Pharmacokinetics, brain penetration, and binding affinities for other receptors and channels will also be evaluated. Specific Aim 3 will assess the effects of these compounds in nicotine self-administration using both fixed-ratio and progressive ratio schedules of reinforcement in nicotine-dependent rats. Specific Aim 4 will assess the effects of the compounds in vivo and in animal models of depression. Initial studies will evaluate the potential side-effect profile of these compounds. Subsequent work will evaluate the effects of the compounds in 6 models of antidepressant activity: the forced swim test in mice and rats, the tail suspension test in mice, the olfactory bulbectomy test in rats, and nicotine and amphetamine withdrawal in rats. The latter test will also provide information about potential therapeutic effects of the compounds on drug withdrawal hypothesized to contribute to relapse. Finally, Specific Aim 5 will attempt to develop and validate a new animal model of depression (7th model) involving olfactory bulbectomy as the inducing condition and brain reward thresholds as the dependent variable, and test putative antidepressant drugs. This integrated multidisciplinary research program focusing on both depression and smoking cessation and capitalizing on the expertise of both Scripps and Novartis scientists will be an innovative approach to the development of new therapeutics for these disorders.